Project Summary Systemic lupus erythematosus (SLE) is a complex autoimmune disease with no known cure. We observed changes of gut microbiota in SLE, including a marked decrease of Lactobacillus spp., in both human and mouse. Our preliminary results showed that increasing Lactobacillus spp. in the gut is beneficial and attenuates SLE-like disease in mice. The goal of this proposal is to mechanistically define the role of a probiotic species, Lactobacillus reuteri (LR), that protects against SLE. Based on extensive preliminary observations, we hypothesize that LR attenuates lupus by strengthening the gut mucosal barrier and modulating the Th17-Treg response. In the proposed studies, we plan to achieve two specific aims to test this hypothesis. Aim 1 is focused on the impact of Lactobacillus spp. on the gut microenvironment in lupus mice. The hypothesis of this aim is that the probiotic bacteria strengthen the gut mucosal barrier by modulating the expression of tight junction proteins. Aim 2 is focused on the mechanism at the systemic level by which Lactobacillus spp. attenuate SLE. The hypothesis of this aim is that the probiotic bacteria attenuates SLE-like disease by increasing systemic TGFb and inducing renal Treg cells. The results of the proposed studies, upon translation to human disease, will identify the key events initiating the cascade that leads to human SLE, and enable development of new therapeutic targets necessary to generate treatments for the disease. Diet and probiotics/prebiotics, known to modify the gut microbiota, have the potential to become cost-effective components of SLE management strategies.